• July 26, 2022

Dr. Paul Monga, Experimental Pathology chairman and Director of the PLRC along with his PLRC Colleagues Dr. Evan Delgado and Dr. Aaron Bell, published a manuscript in Hepatology entitled “Hepatocyte B-Catenin loss is compensated by Insulin-mTORC1 activation to promote liver regeneration”.

Link to Full Text article

Hu S, Cao C, Poddar M, Delgado E, Singh S, Singh-Varma A, Stolz DB, Bell A, Monga SP. Hepatocyte β-Catenin Loss is Compensated by Insulin-mTORC1 Activation to Promote Liver Regeneration. Hepatology. 2022 Jul 21. doi: 10.1002/hep.32680. Epub ahead of print. PMID: 35862186.

  • Paul Monga, MD
  • evan_delgado

Abstract:

Background and aims: Liver regeneration (LR) following partial hepatectomy (PH) occurs via activation of various signaling pathways. Disruption of single pathway can be compensated by activation of another pathway to continue LR. The Wnt-β-catenin pathway is activated early during LR and conditional hepatocyte loss of β-catenin delays LR. Here, we study mechanism of LR in the absence of hepatocyte-β-catenin.

Approach & results: Eight-week-old hepatocyte-specific Ctnnb1 knockout mice (β-cateninΔHC ) were subjected to PH. These animals exhibited decreased hepatocyte proliferation at 40-120h and decreased cumulative 14-day (14d) BrdU labeling of <40%, but all mice survived suggesting compensation. Insulin-mediated mTORC1 activation was uniquely identified in the β-cateninΔHCmice at 72-96h after PH. Deletion of hepatocyte Raptor, a critical mTORC1 partner, in the β-cateninΔHC mice led to progressive hepatic injury and mortality by 30d. PH on early-stage non-morbid RaptorΔHC -β-cateninΔHC mice led to lethality by 12h. RaptorΔHC mice showed progressive hepatic injury, spontaneous LR with β-catenin activation, but died by 40d. PH on early stage non-morbid RaptorΔHC mice was lethal by 48h. Temporal inhibition of insulin receptor and mTORC1 in β-cateninΔHC or controls after PH was achieved by administration of linsitinib at 48h or rapamycin at 60h post-PH, and completely prevented LR leading to lethality by 12-14d.

Conclusions: Insulin-mTORC1 activation compensates for β-catenin loss to enable LR after PH. mTORC1 signaling in hepatocytes itself is critical to both homeostasis and LR and is only partially compensated by β-catenin activation. Dual inhibition of β-catenin and mTOR may have notable untoward hepatotoxic side effects.